1. Field of the Invention
The present invention relates to the field of hemocompatible polymers on hydrophobic porous polymeric materials and, in particular, to hemocompatible substances based upon complexes of heparin deposited upon porous hydrophobic polymers, typically expanded PTFE.
2. Description of Related Art
Continuing advances in medical technology have led to the development and use of numerous medical devices that come into contact with blood or other bodily fluids. To be concrete in our discussion, we focus herein on the particular example of medical devices coming into contact with mammalian blood, particularly human blood, not intending thereby to limit the scope of the present invention to medical devices used exclusively on human patients. In using such devices, it is important that contact of the blood or other bodily fluid with the various components of the medical device not cause therapeutically detrimental alterations to the fluid. In many cases, it is desirable to coat such devices with materials to enhance the biocompatibility of the devices, including coatings that contain bioactive agents, anticoagulants, antimicrobial agents or a variety of other drugs.
It is convenient to consider blood-contacting medical devices as invasive or extra-corporal, although some devices span both classes. Invasive devices are used internally in the treatment of the patient, implanted into the patient for an indefinite or extended period of time or inserted into the patient for relatively brief periods. In many cases, the materials comprising the blood-contacting portions of the invasive device lack sufficient biocompatibility and/or hemocompatibility. This tends to cause changes harmful to the patient in the blood or other fluid coming into contact with the surface (or surfaces) of the device. In such cases it is desirable to coat the surfaces of these devices with materials to enhance the biocompatibility and/or hemocompatibility. Invasive devices that are typically coated with biocompatible or therapeutic substances include implantable artificial orthopedic devices, dental implants, intravascular catheters, emboli capturing systems, epicardial immobilization devices, grafts, stents, intraluminal prosthetic devices and artificial heart valves, among others.
There are also many examples of extra-corporal medical devices that come into contact with blood in which blood is transported and/or processed external to the patient. A few representative examples include cardiopulmonary bypass devices, kidney dialysis equipment, blood oxygenators, separators and defoaming devices, among others. Following such extra-corporal processing, the blood or other bodily fluid may be reintroduced into the patient, transported for storage and/or introduced into another patient. In using such extra-corporal devices, it is important that contact of the blood or other bodily fluid with the various components of the device not cause therapeutically detrimental alterations to the fluid.
It is important in some cases that the surface or the surfaces of the invasive or extra-corporal medical device be coated with substances having therapeutic functions, wherein the coatings may serve several functions in addition to increasing the biocompatibility/hemocompatibility of the surface. Examples of such additional functions include the release of one or more therapeutic agents into the blood in appropriate dosages with appropriate timed-released characteristics and at the proper location within the patient. Thus, the medical device may serve as a convenient delivery platform for the delivery of therapeutically beneficial drugs in addition to its other functions.
One important application related to implantable devices arises in connection with endoluminal stents, particularly as occurring in connection with percutaneous transluminal angioplasty (“PCTA”). Following balloon angioplasty, the lumen of the just-expanded vessel may contract due to several causes. An initial rebound of the walls of the vessel may occur following removal of the balloon. Further thrombosis or restenosis of the blood vessel may occur over time following the angioplasty procedure. The result is often the necessity for another angioplasty procedure or surgical by-pass. Endoluminal stents have been in use for several years in conjunction with a surgical procedure inserting a tube or stent into the vessel following the PCTA procedure to assist in retaining the desired intraluminal opening. A review of the procedure may be found in Endoluminal Stenting by Ulrich Sigwart, Ed. (W. B. Saunders, 1996). A compendium of coronary stents is given in Handbook of Coronary Stents, 3rd Ed. by P. W. Serruys and M. J B Kutryk, Eds. (Martin Dunitz Ltd., 2000). However, even with stenting, occlusions frequently recur within the stent requiring further PCTA or by-pass surgery. Such restenosis following PCTA and the insertion of a stent is sought to be prevented by the use of coated stents. Coatings on stents are often used for the delivery of anticoagulants or other medication that assist in preventing thrombosis and restenosis.
Heparin is an anticoagulant drug composed of a highly sulfated polysaccharide, the principle constituent of which is a glycosaminoglycan. In combination with a protein cofactor, heparin acts as an antithrombin (among other medical effects as described, for example, in Heparin-Binding Proteins, by H. B. Conrad (Academic Press, 1998)). Heparin is an attractive additive to coat on the surface(s) of blood-contacting devices in order to increase the hemocompatibility of the material and/or to release heparin or heparin complexes into the blood to combat thrombosis and restenosis.
The heparin molecule contains numerous hydrophilic groups including hydroxyl, carboxyl, sulfate and sulfamino making underivatized heparin difficult to coat onto hydrophobic polymers. Thus, many types of complexes of heparin with hydrophobic counter ions have been used in order to increase the ability of the heparin-counter ion complex to bind to hydrophobic surfaces. Such counter ions are typically cationic to facilitate binding with anionic heparin, and contain a hydrophobic region to facilitate bonding with the hydrophobic polymer. Typical heparin complexes include, but are not limited to, heparin complex with typically large quaternary ammonium species such as benzylalkonium groups (typically introduced in the form of benzylalkonium chloride), tridodecylmethylammonium chloride (“TDMEC”), and the commercial heparin complex offered by Baxter International under the tradename DURAFLO or DURAFLO II. Herein we denote as “heparin complex” any complex of heparin with a hydrophobic counter ion, typically a relatively large counter ion. Examples of heparin complexes are described in the following U.S. Pat. Nos. 4,654,327; 4,871,357; 5,047,020; 5,069,899; 5,525,348; 5,541,167 (incorporated herein by reference) and references cited therein.
Considerable work has been done in developing coatings for application to various medical devices in which the coatings contain at least one form of heparin or heparin complex. Combinations of heparin and heparin complexes with other drugs, as well as various techniques for tailoring the coating to provide desired drug-release characteristics have been studied. Examples of such work include that of Chen et. al. (incorporated herein by reference), published in J. Vascular Surgery, Vol 22, No. 3 pp 237-247 (September 1995) and the following U.S. Pat. Nos. 4,118,485; 4,678,468; 4,745,105; 4,745,107; 4,895,566; 5,013,717; 5,061,738; 5,135,516; 5,322,659; 5,383,927; 5,417,969; 5,441,759; 5,865,814; 5,876,433; 5,879,697; 5,993,890 (incorporated herein by reference) as well as references cited in the foregoing patents and article, such cited references hereby incorporated a reference into this document.
Implantable medical devices often require some degree of porosity to enable blood to come into contact with underlying tissues, to increase the surface area for delivery of therapeutic substances, or for other purposes. Therefore, porous polymers are widely used in medical devices. The advantages of porosity are not limited to implantable devices, and porous materials are used in extra-corporal devices as well as invasive medical devices. However, the problem of coating with heparin is exacerbated if the hydrophobic polymer is also porous. In addition to binding with the hydrophobic surface, the heparin complex must also penetrate into the interstices of the porous structure of the polymer and bind to all or substantially all of the polymer surface that comes into contact with blood.
Fluorinated polymers are typically chemically unreactive, have low surface energy and are hydrophobic. Such properties are generally favorable for use in medical devices as described, for example by F. H. Silver and D. L. Christiansen in Biomaterials Science and Biocompatibility, (Springer-Verlag, 1999) p. 19. Poly(tetrafluoroethylene), PTFE, is a polymeric material with repeating units of (—CF2CF2—) having numerous commercial uses, including in blood-contacting devices, due in large part to its chemical inertness and desirable physical properties. PTFE in the form of a film or solid has low surface energy and, therefore, is a relatively difficult surface to coat (or “wet”). “Wetting” typically indicates the tendency of a liquid to spread and coat the surface onto which it is placed. The specific relationship between surface energy and the contact angle at the interface between a drop and the surface (the “wetting”) is given in standard references including Physical Chemistry of Surfaces 6th Ed. by A. W. Adams and A. P. Gast (John Wiley, 1997), p. 465 ff. A contact angle between the liquid and the surface greater than approximately 90° typically indicates a non-wetting liquid on that particular surface.
In many medical and non-medical commercial uses, it is desirable to have PTFE in the form of a porous film that retains adequate physical strength for the particular application while not substantially increasing the cost of the material. Expanded PTFE (hereinafter “ePTFE”) is a form of PTFE that has been physically expanded along one or more directions to create a porous form of PTFE having varying amounts of porosity depending on several factors including the specific procedures for performing the mechanical expansion. The porous ePTFE thus created is useful for the manufacture of several commercial products as illustrated (for example) by the work of Gore in U.S. Pat. Nos. 3,953,566 and 4,187,390 and the work of House et. al. in U.S. Pat. No. 6,048,484. Applications to stents include the work of Lewis et. al. (U.S. Pat. No. 5,993,489) and Bley et. al. (U.S. Pat. Nos. 5,674,241 and 5,968,070). The chemical inactivity, and other properties of fluorinated polymers including PTPE and ePTFE, have made them attractive substances for use in many medical and blood-contacting devices. Representative examples include dental implant devices (Scantlebury et. al. U.S. Pat. No. 4,531,916), grafts, stents and intraluminal prosthetic devices (Bley et. al. U.S. Pat. Nos. 5,674,241 and 5,968,070; Goldfarb et. al. U.S. Pat. No. 5,955,016; Lewis et. al. U.S. Pat. No. 5,993,489; Tu et. al. U.S. Pat. No. 6,090,134).
Expanded PTFE is widely used in medical devices and is perhaps one of the most widely used vascular graft materials. In fact, ePTFE has a large range of application in blood-contacting medical devices including, but not limited to, segmental venous replacements, reconstructed veins in organ transplantation, polymer catheters, in-dwelling catheters, urological and coronary stents, covered stents, heart valves, dental implants, orthopedic devices, vascular grafts, synthetic by-pass grafts and other invasive and implantable medical devices. In addition, ePTFE can be used in extra-corporal blood-contacting devices. Examples include, but are not limited to, heart by-pass devices, kidney dialysis equipment, blood oxygenators, defoaming machines, among others.
FIG. 1 is a scanning electron micrograph of porous ePTFE from the work of House et. al. (U.S. Pat. No. 6,048,484). FIGS. 2A and 2B are schematic depictions of two forms of ePTFE showing biaxially oriented fibrils (FIG. 2A), and multiaxially oriented fibrils (FIG. 2B). Both FIGS. 2A and 2B are from House et. al. (supra). Low surface energy characteristic of fluoropolymers and other hydrophobic polymers, in combination with the porosity of ePTFE, make the application of a coating to ePTFE, including coating of the interior surfaces of the pores, a significant challenge. Providing such a coating for ePTFE is one objective of the present invention.
However, when used in a blood-contacting environment, ePTFE tends to be thrombogenic and its porosity may release entrapped gases (which may itself be a source of thrombogenicity as discussed, for example, by Vaun et. al. U.S. Pat. No. 5,181,903). Therefore, considerable effort has gone into the coating of ePTFE to reduce its thrombogenicity and/or provide other therapeutic effects. Hemocompatibility can be achieved by a variety of means, including coating with a hydrophilic, biologically passive, polymer, or by coating with materials having a biologically active component such as heparin or a complex of heparin including the commercially available heparin complex DURAFLO or DURAFLO II (Baxter Healthcare, Inc.). Improved procedures for coating ePTFE with hemocompatible substances, typically substances containing derivatives or complexes of heparin, and the improved hemocompatible materials so produced are among the objects of the present invention. We use the expressions “derivative of heparin” and “complex of heparin” interchangeably herein without distinction to indicate a chemical combination of heparin with a counter ion.
Although fluoropolymers have been among the most commonly used materials for blood-contacting devices, polyurethanes, polyethylene terephthalates (“PETs”) and numerous other fluorinated and non-fluorinated polymers have also found considerable application. Modifications of polyurethanes, PETs and other plastics have included the introduction of coatings for antithrombogenic and anticoagulant properties. PET is an example of a non-fluorinated polymer that is highly hydrophobic and therefore difficult to coat with polar, aqueous materials such as heparin. PTFE is but one example of the general chemical class of fluoropolymer that also includes FEP (fluorinated ethylene propylene), PFA (perfluoroalkyl vinyl ether and tetrafluoroethylene co-polymer), PVDF (polyvinylidenedifluoride), PVF (polyvinylfluoride), PCTFE (polychlorotrifluoroethylene), ETFE (ethylene and tetrafluoroethylene co-polymer) TFB (terpolymer of vinylidenedifluoride, hexafluoropropylene and tetrafluoroethylene) and other fluoropolymers as known in the art and described in many references including, for example, W. Woebcken in Saechtling International Plastics Handbook for the Technologist, Engineer and User, 3rd Ed., (Hanser Publishers, 1995) pp. 234-240, incorporated herein by reference.
Coating the interior regions of highly porous materials such as ePTFE with significant amounts of a hemocompatible substances presents special challenges in addition to the hydrophobicity, deriving in part from the relative inaccessibility of much of the surface to be coated.